The Nuc1 Mutation Affects the Rat Retina and Retinal Vasculature

Abstract

Abstract: : Purpose: The Nuc1 phenotype results from a spontaneous, autosomal dominant mutation in an unknown rat gene. Nuc1 abnormalities are thought to result from alterations in programmed cell death. Characteristic retinal and retinal vascular abnormalities are also present and are described. Methods: Nuc1 homozygous and heterozygous rats are compared to age matched wild type (WT) rats via standard histopathology; fluorescence microscopy of FITC Dextran perfused flatmounts; confocal microscopy, and Affymetrix microarray. Results: As compared to WT: the Nuc1 retina is fully vascularized by P8; by P20 the vasculature is excessive; at P21 there is a near doubling of retinal thickness involving all neural layers; by 2 months microvascular drop–out is evident; by 4 months extravascular and intravascular fluorescent bodies are prevalent (some intravascular bodies result in microvascular obstruction); by 18 months retinal degeneration (thinning) is evident, as are traction retinal detachment and abnormal pre–retinal vessels. The hyaloid vasculature persists throughout the life of the rat. As compared to WT: microarray analysis of Nuc1 homozygous retina at age P25 reveals upregulation of genes related to cell structure/signaling (34.5%), physiological processes (29.8%), cellular processes (26.2%), binding (20.2%) and development (14.3%). By age 87 days a shift in gene expression towards those involved in physiological processes (26.1%), binding (20.4%) and cellular processes (19.7%) has occurred. Conclusions: The Nuc1 phenotype includes retinal degeneration and characteristic retinal vascular abnormalities that are present during development and evolve as the rat matures. Understanding the Nuc1 gene may provide insight into patterns of retinal vascular development, including persistence and regression, as well as neural retinal degeneration that characterizes this mutation.

Keywords: vascular occlusion/vascular occlusive disease • blood supply • retinal neovascularization